Doxorubicin (DOX) is a potent, broad-spectrum chemotherapeutic drug used for treatment of several types of cancers. Despite its effectiveness, it has a wide range of toxic side effects, many of which most likely result from its inherent prooxidant activity. It has been reported that DOX has toxic effects on normal tissues, including brain tissue. In the current study, we investigated the protective effect of osthole isolated from Prangos ferulacea (L.) Lindl. on oxidative stress and apoptosis induced by DOX in PC12 as a neuronal model cell line. PC12 cells were pretreated with osthole 2 h after treatment with different concentrations of DOX. 24 h later, the cell viability, mitochondrial membrane potential (MMP), the activity of caspase-3, the expression ratio of Bax/Bcl-2, and the generation of intracellular ROS were detected. We found that pretreatment with osthole on PC12 cells significantly reduced the loss of cell viability, the activity of caspase-3, the increase in Bax/Bcl-2 ratio, and the generation of intracellular ROS induced by DOX. Moreover, pretreatment with osthole led to an increase in MMP in PC12 cells. In conclusion, our results indicated that pretreatment with nontoxic concentrations of osthole protected PC12 cells from DOX-mediated apoptosis by inhibition of ROS production.
Background and purpose:
Doxorubicin (DOX) as a chemotherapeutic agent has been widely used in the treatment of various types of cancer. However, DOX exerts a toxic effect on normal tissues such as the brain. Furanocoumarins reduce the risk of cardiovascular and brain diseases because of their antioxidant activities. This study has been designed, for the first time, to evaluate the effect of known furanocoumarins oxypeucedanin and isoimperatorin extracted from
Prangos ferulacea
(L.) Lindl on oxidative stress and apoptosis induced by DOX toward pheochromocytoma cell line (PC12).
Experimental approach:
NMR and MASS spectrometers were used to characterize the isolated compounds. The protective effects of isolated compounds on DOX-induced cytotoxicity in PC12 cells were examined by MTT assay. PC12 cells were pretreated with oxypeucedanin and isoimperatorin for 2 and 21 h, respectively, subsequently exposure to DOX at IC
50
concentration. Then, mitochondrial membrane potential (MMP), Bax and Bcl2 mRNA expressions, caspase-3 activation, and the generation of intracellular reactive oxygen species (ROS) were measured after 24 h.
Findings/Results:
Pretreatment with oxypeucedanin and isoimperatorin significantly decreased DOX-induced apoptosis through reduction of caspase-3 activity and ROS generation and an increase in MMP. In addition, our finding showed pretreatment with these compounds leads to regulation of Bcl-2.
Conclusion and implications:
Taken together our observation indicated that oxypeucedanin and isoimperatorin have a protective effect against apoptosis induced by DOX in PC12 cells by inhibition of ROS production.
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